RESEARCH: Role of Spastin in causing HSP

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Work on the role of Spastin in causing HSP by studying

fruit flies (Drosophila), shows that a loss of Spastin

causes " aberrantly stabilized microtubule cytoskeleton

in neurons and defects in synaptic growth and

neurotransmission " .

Interestingly, " (t)he role of Spastin in regulating

neuronal microtubule stability suggests therapeutic

targets for HSP treatment and may provide insight into

neurological disorders linked to microtubule

dysfunction. "

The abstract follows.

Mark

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The Hereditary Spastic Paraplegia Gene, spastin,

Regulates Microtubule Stability to Modulate Synaptic

Structure and Function.

Trotta N, Orso G, Rossetto MG, Daga A, Broadie K.

Department of Biological Sciences, Vanderbilt Kennedy

Center for Research on Human Development, Vanderbilt

University, Nashville, TN 37235 USA.

Background: Hereditary Spastic Paraplegia (HSP) is a

devastating neurological disease causing spastic

weakness of the lower extremities and eventual axonal

degeneration. Over 20 genes have been linked to HSP in

humans; however, mutations in one gene, spastin

(SPG4), are the cause of >40% of all cases. Spastin is

a member of the ATPases associated with diverse

cellular activities (AAA) protein family, and contains

a microtubule interacting and organelle transport

(MIT) domain. Previous work in cell culture has

proposed a role for Spastin in regulating

microtubules. Results: Employing Drosophila transgenic

methods for overexpression and RNA interference

(RNAi), we have investigated the role of Spastin in

vivo. We show that Drosophila Spastin (D-Spastin) is

enriched in axons and synaptic connections. At

neuromuscular junctions (NMJ), Dspastin RNAi causes

morphological undergrowth and reduced synaptic area.

Moreover, Dspastin overexpression reduces synaptic

strength, whereas Dspastin RNAi elevates synaptic

currents. By using antibodies against

posttranslationally modified alpha-Tubulin, we find

that Dspastin regulates microtubule stability.

Functional synaptic defects caused by Dspastin RNAi

and overexpression were pharmacologically alleviated

by agents that destabilize and stabilize microtubules,

respectively. Conclusions: Loss of Dspastin in

Drosophila causes an aberrantly stabilized microtubule

cytoskeleton in neurons and defects in synaptic growth

and neurotransmission. These in vivo data strongly

support previous reports, providing a probable cause

for the neuronal dysfunction in spastin-linked HSP

disease. The role of Spastin in regulating neuronal

microtubule stability suggests therapeutic targets for

HSP treatment and may provide insight into

neurological disorders linked to microtubule

dysfunction.

SOURCE: Curr Biol. 2004 Jul 13;14(13):1135-47.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

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